How Does a Manufacturer Demonstrate Biosimilarity?

There is no single study that will demonstrate biosimilarity. The FDA uses a “totality of the evidence” approach to review applications for biosimilar products. Manufacturers must provide data from:

  • Analytic studies demonstrating that the structure and function of the biosimilar are “highly similar” to the reference product.
  • Animal studies, including assessment of toxicity.
  • A clinical study or studies, including assessment of immunogenicity (whether the biosimilar produces an unwanted immune response) and pharmacokinetics or pharmacodynamics.

The FDA pathway for approving reference biologics emphasizes large clinical studies that establish safety and efficacy. In contrast, the pathway for approving biosimilars places greater emphasis on biological and physicochemical characterizations of the biosimilar molecule, because the safety and efficacy data for the reference product are readily available.

Studies to establish biosimilarity are intended to be conducted in a stepwise manner. Ideally, extensive initial analytic testing demonstrates minimal or no qualitative or quantitative differences in the structure and function of the proposed biosimilar and the reference product. The similarity of the proposed biosimilar and the reference product is confirmed using subsequent animal studies. Any unanswered questions, called “residual uncertainty”, about the clinical safety and efficacy of the proposed biosimilar are addressed in clinical assessments of immunogenicity and pharmacokinetic or pharmacodynamic studies. If residual uncertainty remained after those studies, additional clinical studies would be conducted to confirm the safety and efficacy of the proposed biosimilar.

Ultimately, FDA reviews a totality of evidence to establish that a biosimilar is essentially the same drug as the reference product, and that it will work the same way as the reference product for its approved indications. At the point a biosimilar is approved by the FDA, any differences that exist between the biosimilar and the reference product will have been shown not to affect efficacy or safety.

The illustration provides an overview of how FDA reviews evidence to approve biologics and biosimilars.

Source: Cleveland Clinic